Wider safety window with radiolabeled somatostatin receptor antagonists over agonists.

Objectives To assess, compare and optimize the therapeutic index of the radiolabeled somatostatin (sst) receptor antagonist ¹⁷⁷Lu-OPS201 vs ¹⁷⁷Lu-DOTATATE (agonist). Translational aspects related to peptide receptor radionuclide therapy (PRRT) and imaging are addressed.

Methods ¹⁷⁷Lu-OPS201 and ¹⁷⁷Lu-DOTATATE were compared head-to-head in 2 sst2-expressing xenograft models (HEK-hsst2 & AR42J) in vivo. Biodistribution, pharmacokinetic study and nanoSPECT/CT images were performed. The influence of increasing peptide mass and of octreotide was studied.

Results Besides usual physiological pattern of uptake in sst-positive organs, higher tumor uptake (e.g. ~35%, 4h, p<0.05) and longer tumor residence time (19.1h ¹⁷⁷Lu-OPS201 vs 7.5h ¹⁷⁷Lu-DOTATATE) resulting in a 2.5 times higher tumor dose for the antagonist was found. Despite higher kidney uptake, the tumor-to-kidney dose ratio was increased by 34% in favor of ¹⁷⁷Lu-OPS201. Injection of 10, 200 and 2000pmol of ¹⁷⁷Lu-OPS201 caused no relevant saturation in HEK-hsst2 tumor (19-24%IA/g, 4h, p>0.05) but significant decrease of the background (except renal uptake), as demonstrated by nanoSPECT/CT images. On the contrary, tumor uptake of ¹⁷⁷Lu-DOTATATE decreased by 30% (200pmol) or 45% (2000pmol) (p<0.05). Improved image contrast and higher therapeutic index were confirmed in AR42J xenografts for ¹⁷⁷Lu-OPS201, where tumor uptake did not change from 10 to 200pmol, but reduced significantly at 2000pmol. Co- and pre-injection (24h, 4h and 10min prior to ¹⁷⁷Lu-OPS201) of octreotide i.v. in excess (200-fold), did not influence the distribution of the antagonist, including tumor uptake.

Conclusions Increased tumor uptake, prolonged residence time, favorable differential washout and optimized peptide mass improve the therapeutic index of ¹⁷⁷Lu-OPS201 compared to ¹⁷⁷Lu-DOTATATE. Interruption of sst-analogs before PRRT may not be needed when using radiolabeled antagonists.